Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood
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Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so‐called bile infarcts that correspond to Charcot‐Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon–based imaging of BDL mice was performed with fluorescent bile salts (BS) and non‐BS organic anion analogues. Key findings were followed up by matrix‐assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1‐3 days after BDL, BS concentrations in bile increased and single‐cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a “domino effect” of further death events of neighboring hepatocytes. Bile infarcts provided a trans‐epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS‐overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.
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- Authors
- Ghallab, A., Hofmann, U., Sezgin, S., Vartak, N., Hassan, R., Zaza, A., Godoy, P., Schneider, K. M., Guenther, G., Ahmed, Y. A., Abbas, A. A., Keitel, V., Kuepfer, L., Dooley, S., Lammert, F., Trautwein, C., Spiteller, M., Drasdo, D., Hofmann, A. F., Jansen, P. L. M., Hengstler, J. G., & Reif, R.
- Affiliations
- South Valley University (EG)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- TU Dortmund University (DE)
- Institut national de recherche en sciences et technologies du numérique (FR)
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund,Dortmund,Germany
- Universitätsklinikum Aachen (DE)
- Düsseldorf University Hospital (DE)
- Bayer (Germany) (DE)
- Heidelberg University (DE)
- Saarland University (DE)
- University of California San Diego (US)
- Maastricht University (NL)
- Corresponding author
- Hengstler, Jan G.
- ORCID
- Venue
- Hepatology
- Published
- 2018-11-19
- Volume
- 69
- Issue
- 2
- Pages
- 666-683
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6587841
- OpenAlex
- W2887190751
- Cited by
- 101
- References
- 25
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 12 · 2022: 18 · 2021: 14 · 2020: 18 · 2019: 17 · 2018: 8
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Leibniz-Institut für Arbeitsforschung an der TU Dortmund
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung (031L0051, 031L0045, 031L0055, 031L0052, 031L0037, FKZ 031L0052, 031A355A, 031L0073F)
- State Key Laboratory of Mycology
- Leibniz-Gemeinschaft
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- obstructive cholestasis, bile duct ligation, mitochondrial membrane potential, bile salt toxicity, bile canaliculi, hepatocyte death, cholemic nephropathy
- MeSH terms
- ATP-Binding Cassette Sub-Family B Member 4, Animals, Bile Acids and Salts, Bile Canaliculi, Cholestasis, Disease Models, Animal, Male, Mice, Inbred C57BL, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Hepatocytes, Optical Imaging
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